Disparate effects of first and second generation antipsychotics on cognition in schizophrenia – Findings from the randomized NeSSy trial

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Abstract

Cognitive impairment represents a core feature of schizophrenia. Uncertainty about demonstrable benefits of available antipsychotics on cognition remains an important clinical question relevant to patients’ quality of life. The aim of our multi-center, randomized, double-blind “Neuroleptic Strategy Study” (NeSSy) was to compare the effectiveness of selected antipsychotics, conventionally classified as second- (SGAs) (haloperidol, flupentixol) and first generation antipsychotics (FGAs) (aripiprazole, olanzapine, quetiapine), on quality of life in schizophrenia. The effects on cognitive deficits represented a secondary outcome. We used an innovative double randomization for assignment of treatment group, and followed the patients with a neurocognitive test-battery upon six and 24 weeks of treatment. Psychopathology and quality of life were assessed using CGI, PANSS and SF-36. Assessment of cognitive performance was conducted in 114 of the 136 randomized patients. The SGA group (N = 62) showed beneficial effects of small to moderate effect size on cognition during the initial six weeks of treatment (executive functions, verbal fluency) and at 24 weeks (executive functions, working memory). In contrast, the FGA group (N = 52) showed moderately improved executive function, but a decline in verbal fluency at six weeks, with significant declines of moderate to large effect size in executive function, verbal learning and memory, and verbal fluency at 24 weeks. Our study indicates that SGAs present an advantage over FGAs regarding cognitive function during a medium-term treatment for schizophrenia. The results further emphasize a distinction between progression to detrimental effects of FGAs with prolonged treatment in contrast to more persistent cognitive benefits with SGA treatment.

Introduction

Development of new strategies for ameliorating cognitive impairments in patients with schizophrenia represents a major clinical challenge. Although not included among the criterion “A” of schizophrenia in DSM-5 (Barch et al., 2013), cognitive deficits are nonetheless a core feature of this most severe of psychiatric illnesses (Keefe et al., 2007a), being detectable in almost all individuals with diagnosis of schizophrenia (Keefe and Harvey, 2012). Cognitive impairments often precede the onset of psychosis (Jones et al., 1994) and can persist during the entire course of the illness (Nuechterlein et al., 1992). Furthermore, cognitive impairments are considered the most predictive factor of functional outcome in terms of social, occupational, and living status (Green et al., 2004, Joseph et al., 2017, Kurtz et al., 2008, McClure et al., 2007, Rajji et al., 2014), medication adherence and ability to self-manage medication (Donohoe et al., 2001, Jeste et al., 2003, Patterson et al., 2002), as well as relapse prevention (Trapp et al., 2013). Nevertheless, cognitive impairments per se seem largely independent of the severity of psychotic symptoms (Keefe et al., 2006, Keefe and Harvey, 2012), which may suggest distinct pathomechanisms underlying positive symptoms and cognitive impairments in schizophrenia.

While directed mainly against the positive symptoms, antipsychotic medication can alleviate or exacerbate cognitive impairments in schizophrenia, although the cognitive profiles of different compounds remain poorly defined (Hori et al., 2006). Up to now, numerous investigations in this field targeted the distinction of different antipsychotics regarding their effectiveness against cognitive symptoms without solving this ambiguity. In the majority of such investigations antipsychotics were classified as first (FGA) and second generation (SGA) antipsychotics, despite the contemporary efforts of the scientific community to optimize the psychopharmacological classification by using the neuroscience based classification (NbN) (Zohar et al., 2014). Results of some treatment studies showed absent or small therapeutic effects of FGA on different cognitive domains (Bowie and Harvey, 2005, Mishara and Goldberg, 2004), whereas some studies indicated some pro-cognitive effects of SGA as compared to FGA treatment (Harvey and Keefe, 2001). Indeed, a certain superiority of some SGA has been reported in two recent meta analyses (Desamericq et al., 2014, Zhang et al., 2013), while a larger most recent meta analysis including 37 studies with 3526 patients (Nielsen et al., 2015) has not shown any drug having a uniform positive cognitive profile but detected trends favoring some SGAs (sertindole, ziprasidone, risperidone, quetiapine) towards FGAs.

On the other hand, two prominent and comprehensive studies – the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) (Keefe et al., 2007b, Lieberman et al., 2005) and the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia trail (CUtLASS) (Jones et al., 2006) – reported no differences between FGA and SGA treatment regarding cognitive function. Furthermore, an exploratory analysis of cognitive performance after 18 months in the CATIE trial showed greater cognitive improvement with the FGA perphenazine than with the SGAs olanzapine or risperidone (Keefe et al., 2007a). Nonetheless, due inter alia to several methodological weaknesses subsequently discerned in those studies (Leucht et al., 2009, Tandon et al., 2007), there has been no consensus regarding the treatment of choice for optimal cognitive outcome.

Given this background, we chose to re-examine in the Neuroleptic Strategy Study (NeSSy) the advantages and disadvantages of SGA versus FGA treatment for cognitive performance in schizophrenia patients. The study was conducted without any sponsorship from industry and employed an entirely novel randomization method, which allowed the therapists to have some influence on the treatment selection for individual patients, despite a strictly double blind design (Schulz et al., 2016). We have recently reported the primary outcome parameters, i.e. the change in total quality-of-life scores from baseline to week 24 after randomization – assessed by using the Short Form 36 Health Survey (SF-36) (Tarlov et al., 1989) and the Clinical Global Impression-Improvement scale (CGI-I) (Guy et al., 1976). In brief, SGAs proved significantly superior to FGAs with respect to patient-reported quality of life (Gründer et al., 2016). We now test our secondary hypothesis that SGAs would likewise prove superior to FGAs in ameliorating the cognitive impairments seen in our patients with schizophrenia.

Section snippets

Experimental procedures

After obtaining approval from the responsible human research ethics committees (leading committee: Ethikkommission des Landes Bremen, approval number: EK HB 2009-10-041 FF), this multicenter study was conducted at 14 university and state psychiatric clinics and hospitals in Germany, using a double-blind, double-dummy, randomized design. All directives, guidelines and regulatory requirements, as proposed by the World Medical Association Declaration of Helsinki, the International Conference on

Patients’ characteristics and medication

During the period between April 2010 and May 2013 we screened a total of 2374 patients, of whom 149 met all inclusion criteria. Of these 136 (91%) received at least once the study medication – 63 patients within the FGA-group and 73 within the SGA-group. Statistical analysis for the present manuscript was performed using data from 114 subjects (52 FGA and 62 SGA) among those 136 who had also undergone at least one neuropsychological test battery. The tests were not administered to the remaining

Discussion

In this multicenter study employing a novel double blind, double dummy design, with double randomization, we aimed to compare the effects of typical (FGA) and atypical (SGA) antipsychotics on cognitive functions in schizophrenia. We found beneficial effects on cognition with a small to moderate effect size in the SGA group during the six weeks’ short-term treatment period and at 24 weeks. While FGA treatment initially improved certain executive functions, there was a decline relative to

Acknowledgments

We thank Professor Paul Cumming (Inglewood Biomedical Editing) for the professional editing of the manuscript and his valuable suggestions for improvement.

Role of funding source

The study was funded by the German Federal Ministry of Education and Research, BMBF 01KG0907; ClinicalTrials.gov number, NCT01164059). The BMBF had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Trial registration

German Clinical Trials Register DRKS00000304. http://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00000304

Declaration of individual contributions to the manuscript

Authors MH, GG, JC, BM, GJ, UH, ER and JT designed the study and wrote the protocol. Members of NeSSy study group provided the protocol creation, data collection, literature searches and analyses. Authors MS, TV and JT undertook the statistical analysis, and author TV wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interests

Dr. Gründer has served as a consultant for Allergan (Dublin, Ireland), Boehringer Ingelheim (Ingelheim, Germany), Eli Lilly (Indianapolis, Ind, USA), Janssen-Cilag (Neuss, Germany), Lundbeck (Copenhagen, Denmark), Ono Pharmaceuticals (Osaka, Japan), Otsuka (Chiyoda, Japan), Recordati (Milan, Italy), Roche (Basel, Switzerland), Servier (Paris, France), and Takeda (Osaka, Japan). He has served on the speakers’ bureau of Eli Lilly, Janssen Cilag, Neuraxpharm (Langenfeld, Germany), Lundbeck,

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    The NeSSy Study Group: Stefan Bleich, M.D., Helge Frieling (Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School of Hannover, Hannover); Markus Borgmann, M.D. (Department of Psychiatry, Psychotherapy and Psychosomatics, Brandenburg Medical School, Neuruppin); Vasiliki Breunig-Lyriti, Ph.D., Constanze Schulz, Ph.D., Dmitri Handschuh (University of Bremen, Centre of Competence for Clinical Trials - Biometry, Bremen); Martin Brüne, M.D., Jörg Heller, M.D. (Department of Psychiatry, LWL University Hospital, Ruhr University Bochum, Bochum); Peter Falkai, M.D., Claus Wolff-Menzler, M.D., Thomas Wobrock, M.D. (Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen); Sandra Feyerabend, Wolfgang Gaebel, M.D. (Department of Psychiatry and Psychotherapy, Heinrich-Heine University Düsseldorf, Düsseldorf); Christian Figge, M.D. (Karl-Jaspers Clinic, European Medical School Oldenburg-Groningen, Oldenburg); Jürgen Gallinat, M.D., Marion Lautenschlager, M.D. (Department of Psychiatry and Psychotherapy, Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin); Rainer Kirchhefer, M.D. (Department of Psychiatry and Psychotherapy, Dietrich Bonhoeffer Klinikum, Neubrandenburg); André Kirner, M.D. (Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, RWTH Aachen University, Aachen); Barbara Kowalenko, M.D., Katharina Prumbs (Städtisches Krankenhaus Eisenhüttenstadt, Eisenhüttenstadt); Dieter Naber, M.D. (Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg).

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